1. Field of Invention
This invention relates to compositions and methods useful for the in vivo delivery of substantially water-insoluble drugs, like TAXOL®. The use of specific composition and preparation conditions enables the reproducible production of unusually water-soluble formulation, which can be sterile-filtered. The particulate system produced according to the invention can be converted into a re-dispersible dry powder comprising nanoparticles of drugs. This results in a unique delivery system, in which the pharmacologically active agent is readily bioavailable.
2. Description of Related Art
There are many valuable drugs which practically insoluble in water like the anticancer agent paclitaxel (TAXOL® for Injection Concentrate, Bristol Myers Squibb (BMS)) that reportedly has clinical activity or has been approved for use in a number of human cancers including cancers of the ovary, breast, lung, esophagus, head and neck region, bladder and lymphomas. It is currently approved for the treatment of certain stages of ovarian carcinoma, and non-small cell lung cancer; metastatic breast cancer; and for AIDS-related Kaposi's sarcoma.
A major limitation to the use of paclitaxel is its poor solubility and consequently the BMS formulation (TAXOL®) contains Cremophor® EL as a solubilizing vehicle. Each vial of TAXOL® contains 30 mg of paclitaxel dissolved in Cremophor/ethanol vehicle at a concentration of 6 mg/mL. Prior to intravenous administration, this formulation must be diluted 1:10 in saline to produce a final dosing solution containing 0.6 mg/mL of paclitaxel. Cremophor in this formulation has been linked to severe hypersensitivity reactions in animals (Lorenz et al., 1987, “Histamine Release in Dogs by Cremphor® EL® and its derivatives: Oxethylated oleic acid is the most effective constituent”. Agents Actions 7:63-67, 1987) and humans (Weiss et al., 1990, “Hypersensitivity reactions from Taxol”, J. Clin. Oncol. 8:1263-1268, 1990) and consequently requires premedication of patients with corticosteroids (dexamethasone) and antihistamines. The large dilution results in large volumes of infusion (typical dose 175 mg/m2) in up to one liter and infusion times ranging from three hours to 24 hours. Thus, there is a need for an alternative, less toxic formulation for water-insoluble drugs, such as paclitaxel, and other drugs of same nature.
ABRAXANE® (U.S. Pat. No. 6,537,579) is another paclitaxel formulation. It uses albumin to make small particles of the drug purportedly to make it more bioavailable, but has its own problems of manufacturing because of protein as a carrier more prone to contamination and antigenicity.
Docetaxel is an anti-cancer (“antineoplastic” or “cytotoxic”) chemotherapy drug. This medication is classified as a “plant alkaloid,” a “taxane” and an “antimicrotubule agent.” The drug is prepared in polysorbate and 13% ethanol at the time of administration. The hybrid drug composition of the invention does not requires that all at all and is substantially soluble in water.
Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in people who are refractory to at least one prior systemic therapy (oral) and for the topical treatment of cutaneous lesions in patients with CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies (topical). Bexarotene is a solid, white powder. It is poorly soluble in water; the solubility is estimated to be about 10-50 μM. It is soluble in DMSO at 65 mg/mL and in ethanol at 10 mg/mL with warming. The hybrid drug composition of the invention does not require that at all and is substantially soluble in water.
All-trans-retinoic acid can induce remission in acute promyelocytic leukemia. The molecule is not water-soluble. The hybrid drug composition of the invention is soluble in water.
The other drugs of invention are, for example, acetylsalicylic acid, resveratrol and diazepam.
The hybrids of the invention do not require any of the above material to make it more bioavailable, hence less toxic and more potent. In fact, the technology of the invention can make the drug more effective and less toxic.
The present invention includes compositions and methods useful for the in vivo delivery of substantially water-insoluble drugs, like taxol. The use of specific composition and preparation conditions enables the reproducible production of unusually water-soluble formulations, which can be sterile-filtered. The particulate system produced according to the invention can be converted into a re-dispersible dry powder comprising nanoparticles of drug. This results in a unique delivery system, in which at least part of the pharmacologically active agent is readily bioavailable.
Many drugs for parenteral use, especially those administered intravenously, cause undesirable side effects. These drugs are frequently water-insoluble, and are thus formulated with solubilizing agents, surfactants, solvents, and/or emulsifiers that may be irritating, allergenic, or toxic when administered to patients (see, e.g., Briggs et al., Anesthesis 37:1099 (1982), and Waugh et al., Am. J. Hosp. Pharmacists, 48:1520 (1991)). For example, the chemotherapeutic drug paclitaxel is active against a variety of carcinomas as mentioned above. Paclitaxel, however, has been shown to induce toxicities associated with administration, as well as significant acute and cumulative toxicity, such as myelosuppression, neutropenic fever, anaphylactic reaction, and peripheral neuropathy. Paclitaxel is very poorly water-soluble, and as a result, cannot be practically formulated with water for IV administration. Traditionally, paclitaxel is formulated for IV administration in a solution with polyoxyethylated castor oil (Cremophor) as the primary solvent and high concentrations of ethanol as cosolvent. Cremophor is associated with side effects that can be severe, including anaphylaxis and other hypersensitivity reactions that require pretreatment with corticosteroids, antihistamines, and H2 blockers (see, e.g., Gelderblom et al., Eur. J. of Cancer, 37:1590-1598, (2001)). Similarly, docetaxel is used in treatment of anthracycline-resistant breast cancer, but also has been shown to induce side effects of hypersensitivity and fluid retention that can be severe.
To circumvent problems associated with administration-related side effects of drug formulations, alternative formulations have been developed. For example, ABRAXANE® is a Cremophor-free, protein stabilized formulation of paclitaxel that was developed to resolve or minimize side effects caused by the Cremophor® EL/ethanol formulation. Similar protein-containing formulations have also been developed for other taxanes such as docetaxel and ortataxel, as well as other drugs.
Because protein serves as a good substrate for microbial growth, one major challenge encountered when using these protein-containing formulations is potential microbial contamination. For example, in order to minimize the risk of microbial contamination, the current intravenous formulation of Abraxane® is stored in lyophilized form, and should be injected immediately (e.g., within hours) after it is reconstituted in an aqueous medium. Bacterial growth can result from inadvertent contamination in a container containing a single dosage. Bacterial contamination is even more of a problem when multiple dosage withdrawals from the containers are needed.
Antibacterial agents such as EDTA, pentetate, or sulfites containing agents are generally known and used in pharmaceutical compositions. See, e.g., U.S. Pat. Nos. 5,714,520, 5,731,355, 5,731,356, 6,028,108, 6,100,302, 6,147,122, 6,177,477, 6,399,087, and 6,469,069, International Patent Application No. WO 99/39696, and U.S. Pat. Pub. No. 20050004002. Many of the antibacterial agents, however, are considerably toxic. For example, the addition of sulfites to drug formulations present potential adverse effects to the pediatric population and for those in the general population who are allergic to sulfur. See, e.g., Baker et al., Anesthesiology, 103(4):1-17 (2005); Mirejovsky, Am. J. Health Syst. Pharm., 58:1047 (2001). The toxicities of these antibacterial agents become a significant problem in formulating protein-containing pharmaceutical drug compositions, which frequently require more antimicrobial agents than non-protein containing formulations do in order to counter significant microbial growth therein.
Furthermore, many antimicrobial agents are known to interact with proteins and cause stability problems such as aggregation. See, e.g., Lam et al., Pharm. Res. 14:725-729 (1997). The effect of antimicrobial agents on protein stability raises a difficult issue in formulating protein-containing compositions of poorly water-soluble pharmaceutical agents, since proper configuration of proteins is generally required for stabilizing poorly water-soluble pharmaceutical agents in the composition.
There is therefore a need to develop a new strategy for poorly water-soluble pharmaceutical agents and which do not cause unacceptable toxicological effects upon administration.
There is need of developing a formulation which acts on the disease on multiple pathway of action while making the drug more bioavailable.
All references cited herein are incorporated herein by reference in their entireties.